PROJECT SUMMARY Alzheimer?s Disease is a neurodegenerative disease characterized by a progressive decline in cognitive function and a corresponding accumulation of ?-amyloid plaques and neurofibrillary tangles, the two hallmark pathologies. Drugs currently available to AD patients manage the disease symptoms by improving neuronal activity, but efficacy diminishes as the disease advances. In tauopathies such as AD, the accumulation of tau correlates closely with neuronal loss and decline of cognitive function. The novel targeted approach to AD drug development proposed by Aquinnah Pharmaceuticals stems from discoveries made by Dr. Ben Wolozin (Boston University and co-founder of Aquinnah) and his laboratory, in which tau pathology (in both AD brain samples and animal models) was observed in stress granules (SG). Aquinnah is advancing these compelling findings to further the development of novel molecules that inhibit the formation of tau-SGs as a novel treatment for AD that were identified in SBIR Phase I. The overall objective of this SBIR Phase II application is to perform a medicinal chemistry hit-to-lead and lead optimization program to advance our novel compounds for the treatment of AD.